1. Field of the Invention
The present application relates to derivatives of 8-epiblechnic acid and use thereof in treating a disease related to endothelin receptor A or endothelin-1 (ET-1) over-expression.
2. Description of the Related Art
Cancer arises in a multi-step process with complex formative causes. ET-1 participates in the formation and development of many types of tumors via endothelin receptor type A (ETAR) and endothelin receptor type B (ETBR), such as prostate cancer, ovarian cancer, renal cancer, lung cancer, colon cancer, melanoma, cervical cancer, bone cancer, breast cancer, Kaposi's sarcoma, and some central nervous system tumors.
ET-1 and its receptors (ETAR and ETBR) are over-expressed in breast carcinomas and appear to influence tumor growth and progression (British Journal of Cancer (2004) 91, 434-440).
Clinical tests have proven that endothelin receptor type A antagonist (Atrasentan, ABT-627) can treat prostate cancer. In summary, ET-1 plays an important role in the physiological mechanism of cancer, and can promote tumor growth via specific endothelin receptors. Because of this, endothelin receptor antagonists provide a novel and important means for treating cancers.
Lithospermic acid B (Salvianolic acid B, Sal-B) has been identified as an active component in an extract of Salvia miltiorrhiza radix that was shown to exhibit endothelium-dependent vasodilatation in the aorta and may be useful in the treatment of hypertension (see Kamata, et al., 1993, Gen. Pharmacol. 24, 977-981). Sal-B is a water-soluble phenolic acid extracted from Salvia miltiorrhiza; its anti-tumor efficacy has been disclosed in Chinese patent application No. CN1408353A.
It has been found that the blood of hypertension patients contains higher levels of ET-1 than that of normal persons, and it has been discovered that ET-1 has a major influence on the developments of cardiovascular diseases in humans, such as hypertension, atherosclerosis, and myocardial infarction (Schmitz-Spanke, 2000). Other researchers have found that, after treating rats with the ETAR antagonist BQ-123 in the animal model of induced-hypertension, the symptoms of hypertension and ventricular enlargement can be eased. (Yamazaki, 1996; Barton, 1998; Matsumura, 1999; Dao, 2001; Park, 2001).
There is still a need to develop the analogs of Sal-B as the drugs to sufficiently treat the diseases related to the over-expression of ET-1 or endothelin receptor via inhibiting the expressions of endothelin receptors. The diseases include tumor growth and metastasis, as well as cardiovascular diseases, e.g. hypertension, atherosclerosis, and myocardial infarction.